Yb(OTf)3-catalyzed one-pot synthesis of β-lactams from silyl ketene thioacetals by a two- or a three-component reaction

Full text of DOI:10.1021/jo960844u

J . Org. Chem. 1996, 61, 8293-8296
8293
Notes
afford mixtures of trans (t) and cis (c) â-lactams 11t,c-
19t,c (Scheme 1).6
Yb(OTf)3-Ca ta lyzed On e-P ot Syn th esis of
â-La cta m s fr om Silyl Keten e Th ioa ceta ls by
a Tw o- or a Th r ee-Com p on en t Rea ction †
Reaction conditions were established studying the
condensation of SKTA 1 with imines 6 and 7. The
results, collected in Table 1, show that acetonitrile as
solvent secured the best stereoselectivity (Table 1, entries
2 and 7). A better yield can be obtained by either
extending the reaction time (Table 1, entry 8) or increas-
ing the temperature (Table 1, entry 9). However, the
latter change is detrimental for the stereoselection.
Remarkably, Yb(OTf)3 can be recovered from the aqueous
phase during reaction workup and can be recycled to
afford the product virtually in the same yield and
stereoselection (Table 1, entry 3).7 A switch from aceto-
nitrile to nitromethane positively influences the yield but
negatively affects the stereocontrol (Table 1, entries 4 and
10). The use of a 50:50 mixture of these solvents leaves
the yield unchanged and depresses the t:c ratio (Table
1, entry 5).8 The reaction could also be performed in
dichloromethane (Table 1, entry 1) and in methanol
(Table 1, entry 6).
Rita Annunziata, Mauro Cinquini,* Franco Cozzi,*
Valentina Molteni, and Olaf Schupp
Centro C.N.R. and Dipartimento di Chimica Organica e
Industriale, via Golgi 19, 20133 Milano, Italy
Received May 7, 1996
The Lewis acid (LA)-catalyzed addition of silyl ketene
acetals to imines is reported to afford â-amino esters.1
When this approach is used en route to â-lactams, a two-
step procedure involving condensation and 2-azetidinone
ring closure is therefore required.1c,h,k
We2 and others3 recently described an one-pot synthe-
sis of â-lactams by condensation of silyl ketene thioacetals
(SKTA) derived from 2-pyridyl thioesters with imines4
carried out in the presence of stoichiometric amounts of
LA. We now report that a 10% molar amount of Yb(OTf)3
(OTf ) OSO2CF3)1j-m is able to promote the addition of
SKTA to imines in a reaction that represents the first
catalytic one-step synthesis of â-lactams. An extremely
simple three-component version of this process that
allows the 2-azetidinone ring formation from a mixture
of an aldehyde, an amine, and a SKTA has also been
realized.
The condensations of SKTA 1 with imines 8-10 and
of SKTA 2-5 with imine 6 to give â-lactams 13t,c-19t,c
were then studied to establish the scope and limitations
of this process. The data, collected in Table 2, show that
the reaction can be extended to imines derived from
heteroaromatic and aliphatic aldehydes as well as to
other alkyl-substituted and oxygen-substituted SKTA.
The chemical yields range from moderate to good and
become low in the case of the sterically demanding SKTA
3 and of the silyloxy derivative 5. With the oxygenated
SKTA 4 and 5, a dependence of the yield on the isomeric
composition of SKTA was also observed.9 The diastereo-
selectivity is high for the reactions involving alkyl-
substituted (E)-SKTA 1-32 with (E)-imines 6-810 and
is poor when configurationally unstable SKTA 4 and 52
or aliphatic imines were employed (see Figure 1).10,11
SKTA 1-52 were reacted with 2.0 mol equiv of imines
5
6-10 in the presence of 0.1 mol equiv of Yb(OTf)3 to
† Dedicated to Professor Paolo Gru¨nanger on the occasion of his 70th
birthday.
(1) (a) Ikeda, K.; Achiwa, K.; Sekiya, M. Tetrahedron Lett. 1983,
24, 913 and 4707. (b) Morimoto, T.; Sekiya, M. Chem. Lett. 1985, 1371.
(c) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987, 28, 4331
and 4335. (d) Mukaiyama, T.; Kashiwagi, K.; Matsui, S. Chem. Lett.
1989, 1397. (e) Mukaiyama, T.; Akamatsu, H.; Han, J . S. Chem. Lett.
1990, 889. (f) Soga, T.; Takenoshita, H.; Yamada, M.; Mukaiyama, T.
Bull. Chem. Soc. J pn. 1990, 63, 3122. (g) Mladenova, M.; Bellassoued,
M. Synth. Commun. 1993, 23, 725. (h) Onaka, M.; Ohno, R.; Yanagiya,
N.; Izumi, Y. Synlett 1993, 141. (i) Ishiara, K.; Funahashi, M.; Hanaki,
N.; Miyata, M.; Yamamoto, H. Synlett 1994, 963. (j) Kobayashi, S.;
Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya, I. Synlett 1995, 233.
(k) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995, 36,
5773. (l) Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara,
Y. Synthesis 1995, 801. For examples of Yb(OTf)3 catalyzed allylation
of imines see: (m) Bellucci, C.; Cozzi, P. G.; Umani-Ronchi, A.
Tetrahedron Lett. 1995, 36, 7289. (n) Cozzi, P. G.; Di Simone, B.;
Umani-Ronchi, A. Tetrahedron Lett. 1996, 37, 1691.
It was recently demonstrated15 that the Mukaiyama-
type condensation catalyzed by metal triflates can actu-
ally be promoted by an in situ generated R3SiOTf species.
This could also be the case in our reaction, since the
condensation of SKTA 1 with imine 6 in the presence of
(5) Two different samples of commercially available (Aldrich) Yb(OTf)3
were employed and used without the need of any further purification.
When purchased, the first sample contained ca. 1.5 mol and the second
one ca. 2.3 mol of water/mole of Yb(OTf)3. However, they behave
identically. Since Yb(OTf)3 is hygroscopic, its water content can
increase.
(6) Trans:cis ratios were determined by 300 MHz 1H NMR analysis
of the crude products (J trans ) 2.0-2.5 Hz; J cis ) 5.0-6.0 Hz).
(7) Kobayashi, S. Synlett 1994, 689.
(2) Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni, V.; Schupp, O.
Tetrahedron 1996, 52, 2573.
(3) (a) Hirai, K.; Iwano, Y.; Mikoshiba, I.; Koyama, H.; Nishi, T.
Heterocycles 1994, 38, 277. (b) Hirai, K.; Homma, H.; Mikoshiba, I.
Heterocycles 1994, 38, 281.
(8) When SKTA 1 was exposed to a catalytic amount of Yb(OTf)3 in
acetonitrile-d3 or nitromethane-d3, slow formation of the corresponding
2-pyridyl thioester occurred. The proton required by this conversion
should derive either from traces of water present in the solvent or from
the water associated with Yb(OTf)3 (see ref 5).
(9) For a similar observation on the different reactivity of (E) and
(Z) isomers of oxygenated SKTA see: Kobayashi, S.; Horibe, M.;
Achiya, I. Tetrahedron Lett. 1995, 36, 3173 and references therein.
(10) Imines of aromatic aldehydes are known to exist and react in
the (E) configuration, while those of aliphatic aldehydes generally exist
as mixtures of (E) and (Z) isomers. For a review see: McCarty, C. G.
In The Chemistry of the C-N Double Bond; Patai, S., Ed.; Interscience:
New York, 1970; Chapter 9, pp 363-464. Aromatic imines such as 6
were shown not to isomerize even in the presence of strong LA (see
ref 4).
(4) The reaction of various metal enolates of 2-pyridyl thioesters with
imines affords â-lactams in an one-pot process. (a) Titanium enolates:
Annunziata, R.; Benaglia, M.; Chiovato, A.; Cinquini, M.; Cozzi, F.
Tetrahedron 1995, 51, 10025 and references therein. (b) Tin enolates:
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L.
Tetrahedron 1994, 50, 5821 and references therein. (c) Boron eno-
lates: Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Molteni,
V.Tetrahedron 1995, 51, 8941 and references therein. (d) Aluminum
enolates: Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Molteni, V. Tetrahedron 1996, 52, 2583. In a control experiment it was
found that Yb(OTf)3 does not promote the reaction between 2-pyridyl
thioesters and imines.
S0022-3263(96)00844-4 CCC: $12.00 © 1996 American Chemical Society

8294 J . Org. Chem., Vol. 61, No. 23, 1996
Notes
Sch em e 1a
F igu r e 1.
in which the imine was generated in situ.1k We were
pleased to find that when a mixture of Yb(OTf)3 (0.1 mol
equiv), an aldehyde (2.0 mol equiv), 4-methoxyaniline (2.0
mol equiv), and SKTA 1, 2, or 4 (1.0 mol equiv) in
nitromethane was stirred at room temperature for 15 h,
â-lactams 11t,c-14t,c, 16t,c, and 18t,c were obtained
as mixtures of trans and cis isomers in fair to high
isolated yield (Table 3).17
a
Abbreviations: TBDMS, t-BuMe2Si; Py, 2-pyridyl; PMP,
4-MeOPh; Bn, PhCH2; TBDPS, t-BuPh2Si.
Remarkably, no dehydrating agent was required, the
addition of MgSO4 leading to identical yields and
1k
Ta ble 1. Syn th esis of â-La cta m s 11t,c a n d 12t,c fr om
SKTA (E)-1 a n d im in es 6 a n d 7a
isomeric ratios. It is also worth mentioning that when
TBDMSOTf was used as catalyst in the three-component
reaction both yields and stereoselectivity decreased (Table
3, entry 2 vs 1).18,19
The use of enantiomerically pure reagents was also
investigated to achieve control of the absolute configu-
ration of the newly formed stereocenters (Scheme 2).
entry imine
solvent
CH2Cl2
CH3CN
CH3CN
CH3NO2
CH3NO2/CH3CN
CH3OH
CH3CN
CH3CN
product yieldb (%) t:c ratioc
1
2
6
6
6
6
6
6
7
7
7
7
11t,c
11t,c
11t,c
11t,c
11t,c
11t,c
12t,c
12t,c
12t,c
12t,c
77
63
62d
99
65
58
27
42e
64f
90
66:34
97:3
95:5
89:11
93:7
77:23
98:2
98:2
84:16
60:40
3
4
5
6
7
8
(11) The trans steroeselectivity observed in the synthesis of â-lac-
tams 11-13, 16, and 17 can be explained by antiperiplanar model A12,13
(Figure 1), which features an (E)-SKTA in the so called “pin-wheel”
conformation14 and an (E)-imine activated by the LA. If it is assumed
that the R/R1 steric interaction in A is similar to the R/PMP one present
in B, model A appears to be favored over model B, that leads to cis
products, because the R1/OTBDMS interaction present in A should be
less sterically demanding than the R1/SPy one present in B (Figure
1).2,12
(12) Antiperiplanar transition states have been found to be preferred
over their synclinal counterparts in an intramolecular LA-catalyzed
aldol condensation: Denmark, S. E.; Lee, W. J . Org. Chem. 1994, 59,
707. Models analogous to A and B have been used to explain the
stereoselectivity of Mukaiyama aldol condensation in general and of
the aldol reaction of SKTA 1 in particular: Suh, K.-H.; Choo, D.-J .
Tetrahedron Lett. 1995, 36, 6109. For a review see: Gennari, C. In
Comprehensive Organic Synthesis; Trost, B., Fleming, I., Heathcock,
C. H., Eds.; Pergamon Press: Oxford, 1991; Paart 2, Vol. 2, pp 629-
660.
9
10
CH3CN
CH3NO2
a
SKTA:Yb(OTf)3:imine ratio 1.0:0.1:2.0; reaction temperature
b
20 °C; reaction time 15 h, unless otherwise stated. Isolated yield
after flash chromatography. c As determined by 300 MHz 1H NMR
d
spectroscopy on the crude products. This reaction was performed
with a sample of catalyst that was recovered from a previous
reaction (entry 2) and recycled. e Reaction time 72 h. f Reaction
temperature 60 °C.
Ta ble 2. Syn th esis of â-La cta m s 13t,c-19t,c fr om SKTA
1-5 a n d im in es 6 a n d 8-10
SKTAa
imine
solventb
product
yieldc (%) t:c ratiod
1
1
1
1
8
8
9
10
6
6
CH3CN
CH3NO2
CH3CN
CH3NO2
CH3CN
CH3NO2
CH3CN
CH3CN
13t,c
13t,c
14t,c
15t,c
16t,c
17t,c
18t,c
19t,c
29
57
89
36
62
16
49
21
96:4
87:13
37:63
63:37
95:5
98:2
60:40
40:60
(13) NMR experiments showed that Yb(OTf)3 coordinates the imine
but not the pyridine nitrogen. Therefore, a seven-membered cyclic
transition state as that proposed for the TiCl4 addition of SKTA 1-3
to imines (see ref 2) should be ruled out.
2
3
(14) NMR experiments (see ref 2) showed that (E)-SKTA 1-3 adopt
this conformation in solution. For similar observations see: Wilcox,
C. S.; Babston, R. E. J . Org. Chem. 1984, 49, 1451. Babston, R. E.;
Lynch, V.; Wilcox, C. S. Tetrahedron Lett. 1989, 30, 447.
(15) Hollis, T. K.; Bosnich, B. J . Am. Chem. Soc. 1995, 117, 4570.
For a recent example of imine activation by Me3SiCl see: Wang, D.-
E.; Dai, X.-L.; Hou, X.-L. Tetrahedron Lett. 1995, 36, 8649.
(16) (a) Kobayashi, S.; Ishitani, H.; Nagayama, S. Chem. Lett. 1995,
423. (b) Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995, 1195.
(c) Ishitani, H.; Nagayama, S. Kobayashi, S. J . Org. Chem. 1996, 61,
1902.
(17) The three-component reaction can be explained either by a
SKTA addition to imine that is faster than that to the aldehyde or by
an extremely fast imine formation that de facto prevents any addition
of SKTA to the aldehyde. Two experimental observations seem to
support the first hypothesis. First, in ancillary NMR experiments
carried out in acetonitrile-d3, it was shown that Yb(OTf)3 strongly
coordinates the imine 6 nitrogen and poorly coordinates the benzal-
dehyde oxygen (the sCHdNs proton of imine 6 and of the 6 +
Yb(OTf)3 adduct resonates at 8.57 and at 9.00 ppm, respectively; the
sCHdO proton of benzaldehyde and of the benzaldehyde + Yb(OTf)3
adduct resonates at 10.0 and at 9.85 ppm, respectively). Second, in
the presence of Yb(OTf)3 the formation of imine 6 requires 3 h to occur
at 60% yield at rt. As suggest by one of the reviewers, other possible
scenarios involve imine fast formation and higher reactivity or a
reversible SKTA additon to aldehydes and an irreversible one to
imines.
4e
5f
6
6
a
b
(E)/(Z) ratio >98:2 unless otherwise stated. In CH3CN:
reaction conditions of entry 2, Table 1. In CH3NO2: reaction
conditions of entry 4, Table 1. c Isolated yield after flash chroma-
tography. As determined by 300 MHz 1H NMR spectroscopy on
d
the crude products. e (E)/(Z) ratio of starting SKTA ) 40:60. With
a (E)/(Z) ratio ) 90:10, 20% yield, t:c ratio 50:50. With a (E)/(Z)
ratio ) 60:40 in CH3NO2, 36% yield, t:c ratio 60:40. f (E)/(Z) ratio
of starting SKTA ) 92:8. With (E)/(Z) ratio ) 4:96 no reaction
was observed.
0.1 mol equiv of TBDMSOTf afforded â-lactam 11 in 76%
yield as a 95:5 t:c mixture in acetonitrile and in 86% yield
as an 89:11 t:c mixture in nitromethane, respectively (cf.
entries 3 and 4, Table 1). In the latter solvent, however,
the product was contaminated by the compound derived
from addition of nitromethane to imine 6, which was not
formed in the Yb(OTf)3-catalyzed reaction.
Trying to make this simple â-lactam synthesis even
more simple, and keeping in mind the great ability of
Yb(OTf)3 to activate imines toward nucleophilic
attack,1j-m,16 a three-component reaction was attempted
(18) In this synthesis of 11 the adduct derived from the condensation
of nitromethane with imine 6 was obtained in 40% yield.

Notes
J . Org. Chem., Vol. 61, No. 23, 1996 8295
â-lactams 2420 having the 3,4-cis-4,4′-syn (c,s), 3,4-trans-
4,4′-syn (t,s), and 3,4-cis-4,4′-anti (c,a ) configurations,
respectively, as assigned by comparison of 1H NMR
data.20,24,25
Ta ble 3. Th r ee-Com p on en t Syn th esis of â-La cta m s
11t,c-14t,c, 16t,c, a n d 18t,c fr om SKTA 1, 2, a n d 4 a n d in
a
Situ Gen er a ted Im in es 6-9 in CH3NO2
entry
SKTAb
imine
product
yieldc (%)
t:c ratiod
1e
2
3
4
5
1
1f
1
1
1
2
4
6
6
7
8
9
6
6
11t,c
11t,c
12t,c
13t,c
14t,c
16t,c
18t,c
82
56
69
54
90
78
59
90:10
82:18
60:40
87:13
40:60
95:5
Finally, when SKTA 2 was reacted with imine (R)-25
in nitromethane a 46:39:15 mixture of two trans and one
cis isomers of â-lactam 26 was obtained in 72% yield.26
Therefore, the reactions with chiral reagents occurred
either with good stereocontrol but in poor yield (as for
â-lactam 22) or with scarce stereoselectivity but in high
yield (as for 24 and 26). As a consequence, this catalytic
â-lactam synthesis does not appear to be the method of
choice for the preparation of enantiomerically pure
compounds starting from chiral substrates.27
6
7
69:31
a
SKTA:Yb(OTf)3:aldehyde:amine ratio 1.0:0.1:2.0:2.0; reaction
temperature 20 °C; reaction time 15 h, unless otherwise stated.
(E)/(Z) ratios: for 1 and 2, >98:2; for 4, 40:60. c Isolated yield
b
d
after flash chromatography. As determined by 300 MHz 1H NMR
spectroscopy on the crude products. e In CH3CN this reaction gave
11t,c in 48% yield and a 96:4 t:c ratio. f With TBDMSOTf as
catalyst.
The reaction of SKTA 1 with imine 6 catalyzed by two
recently described28,29 chirally modified Yb reagents was
also studied, but this approach gave disappointing re-
sults. Indeed, in the presence of the reagent prepared
from Yb(OTf)3, (R)-binaphthol, and a tertiary amine28 the
reaction did not occur; on the other hand, when the bis-
triflamide of (1S,2S)-1,2-diphenylethylendiamine was
used as Yb ligand,29 â-lactam 11 was obtained in 36%
yield as a 86:14 mixture of virtually racemic trans and
cis isomers.
Sch em e 2a
In conclusion, the first catalytic one-pot synthesis of
â-lactams has been realized by a two- or a three-
component reaction in which Yb(OTf)3 catalyzes the
addition of various SKTA to pre-formed imines (two-
component reaction) or to imines generated in situ from
aldehydes and 4-methoxyaniline (three-component reac-
tion). The products were formed in fair to high yields
and with variable degrees of trans/ cis stereoselectivity,
which depend on the SKTA and the imine structures.
Extension of the reaction to enantiomerically pure re-
agents had a limited success, as had the use of chirally
modified Yb species. Work is underway in our labora-
tories to apply this method to a solid-phase synthesis of
â-lactams and to exploit the three-component reaction
in the field of combinatorial chemistry.30
a
Abbreviations: see Scheme 1.
Reaction of SKTA (R)-20,2 derived from (R)-methyl 3-hy-
droxybutyrate via the corresponding O-silyl-protected
2-pyridyl-thioester,20 with bis-imine 2121,22 in nitromethane
afforded, after acidic workup,22 â-lactam 22c,a as a single
cis isomer in a poor 24% overall yield. The configuration
of this product was determined as 3,4-cis-3,3′-anti (c,a )
by checking that its 1H NMR spectrum was consistent
with the proposed structure and different from those of
its 3,4-trans-3,3′-anti, 3,4-trans-3,3′-syn, and 3,4-cis-3,3′-
syn isomers reported in the literature23 (see Scheme 2
for numbering).
(23) Georg, G. I.; Kant, J .; Gill, H. S. J . Am. Chem. Soc. 1987, 109,
1129 and references cited therein. It must be noted that â-lactam 22c,a
features the 3,3′-anti configuration and the functional groups required
for the synthesis of the carbapenem antibiotics of the thienamycin
family.
(24) When this reaction was carried out in dichloromethane the yield
was 64% and the c,s:t,s:c,a :t,a isomer ratio was 17:21:27:35. In
acetonitrile, the yield was 46% and the isomer ratio 55:30:5:10.
(25) The reactions of SKTA 2 with the N-4-(methoxyphenyl)imines
derived from (S)-2-(benzyloxy)- and (S)-2-[(tert-butyldimethylsilyl)oxy]-
propanal occurred in low yields (28 and 18%, respectively) and poor
stereocontrol.
(26) For recent examples of â-lactam synthesis by enolate additon
to imines bearing chiral auxiliaries, see ref 4a and references cited
therein. For the use of imine (R)-25, see: Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron 1994, 50, 9471.
In that work, other imines were employed that gave better results than
(R)-25. These, however, did not give any satisfactory results in the
Yb(OTf)3-catalyzed reaction described here.
(27) For instance, the use of imines such as 23 or of the 2-pyridyl
thioester precursor of 20 in the TiCl4-promoted stereoselective syn-
thesis of â-lactams gave much more satisfactory results: see ref 20.
(28) (a) Kobayashi, S.; Ishitani, H. J . Am. Chem. Soc. 1994, 116,
4083. (b) Kobayashi, S.; Ishitani, H.; Hachiya, I.; Araki, M. Tetrahedron
1994, 50, 11637.
Condensation of SKTA 2 with imine (S)-2320 in ni-
tromethane gave in 86% yield a 54:36:10 mixture of
(19) â-Lactam 11t,c can be obtained from SKTA 1 and imine 6 in
nitromethane also in the absence of the catalyst (two-component
reaction: 22% yield; three-component reaction: 8% yield). An uncata-
lyzed Mukaiyama-Michael addition of a silyl ketene acetal to an
unsaturated ketone in nitromethane has been previously reported:
RajanBabu, V. T. J . Org. Chem. 1984, 49, 2083. The reaction of
benzaldehyde with nitromethane rather than with a silyl ketene acetal
in a Rh-catalyzed aldol process has been recently described: Kiyooka,
S.-I.; Tsutui, T.; Maeda, H.; Kaneko, Y.; Isobe, K. Tetrahedron Lett.
1995, 36, 6531.
(20) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G. J . Org.
Chem. 1992, 57, 4155.
(21) Kliegman, J . M.; Barnes, R. K. J . Org. Chem. 1970, 35, 3140.
(22) For an example of the use of imine 21 in the synthesis of
4-formyl-substituted â-lactams see: Alcaide, B.; Martin-Cantalejo, Y.;
Perez-Castells, J .; Rodriguez-Lopez, J .; Sierra, M. A.; Monge, A.; Perez-
Garcia, V. J . Org. Chem. 1992, 57, 5921.
(29) Uotsu, K.; Sasai, H.; Shibasaki, M. Tetrahedron: Asymmetry
1995, 6, 71.
(30) The first example of solid-phase combinatorial â-lactam syn-
thesis has just been published: Ruhland, B.; Bhandari, A.; Gordon,
E. M.; Gallop, M. A. J . Am. Chem. Soc. 1996, 118, 253. This method
relies on a simple synthesis of imines immobilized on a polymeric
matrix: Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 36, 2937.

8296 J . Org. Chem., Vol. 61, No. 23, 1996
Notes
1-(4′-Meth oxyp h en yl)-3-m eth yl-4-(2-m eth ylp r op yl)a zeti-
d in -2-on e (15t,c). The 63:37 trans:cis diastereoisomeric mix-
Exp er im en ta l Section
SKTA 1-5 and 20 were known compounds.2 Imines 6-10,
21,21 23,20 and 2526 were prepared by stirring equimolar amounts
of aldehyde and the required amine in dichloromethane in the
presence of MgSO4 at rt for 2-12 h; filtration and removal of
the solvent in vacuum gave the crude imines that were used as
such.10
ture was an oil. IR: 1740 cm-1
. Anal. Calcd for C15H21NO2:
C, 72.84; H, 8.56; N, 5.66. Found: C, 72.69; H, 8.63; N, 5.70.
1
Selected H NMR data of 15t (CDCl3): δ 3.63 (1H, m); 2.88 (1H,
dq, J ) 2.1, 6.7 Hz); 2.00 and 1.37 (2H, AB system, J ) 5.0,
11.0 Hz).1.37, (3H, d, J ) 6.7 Hz). 13C NMR data of 15t
(CDCl3): δ 167.6, 156.0, 131.0, 118.7, 114.4, 58.8, 55.5, 50.7, 41.0,
Gen er a l P r oced u r e for th e Yb(OTf)3-Ca ta lyzed Tw o-
Com p on en t â-La cta m Syn th esis. The preparation of 1-(4′-
methoxyphenyl)-3-methyl-4-phenylazetidin-2-one (11t ,c) in
CH3CN is illustrative of the procedure. To a stirred solution of
Yb(OTf)3 (0.031 g, 0.05 mmol) in anhydrous CH3CN (2 mL) kept
at rt under nitrogen was added SKTA 1 (0.141 g, 0.5 mmol) in
CH3CN (2 mL) via a cannula, immediately followed by imine 6
(0.211 g, 1 mmol) in CH3CN (2 mL). The mixture was stirred
at rt for 15 h. Et2O (10 mL) and water (5 mL) were then added,
and the two phases were separated. The aqueous phase was
extracted with Et2O, and the combined organic phase was dried
over sodium sulfate, filtered, and evaporated in vacuum. The
1
25.8, 23.3, 22.4, 13.4. Selected H NMR data of 15c (CDCl3): δ
4.10 (1H, m); 3.40 (1H, dq, J ) 5.4, 7.0 Hz); 1.73 and 1.50 (2H,
AB system, J ) 3.0, 7.0 Hz).1.27, (3H, d, J ) 7.0 Hz). 13C NMR
data of 15c (CDCl3): δ 168.0, 156.0, 130.9, 118.9, 114.4, 55.5,
53.5, 46.6, 36.1, 29.6, 23.3, 22.2, 9.1
(3S,3′R,4R) 3-[1[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-
eth yl]-4-for m yl-1-(4′-m eth oxyph en yl)azetidin -2-on e (22c,a).
This compound was a light yellow oil that had [R]22D 47.8 (c 0.56
in CHCl3). IR: 1740, 1720 cm-1. Anal. Calcd for C19H29NO4Si:
C, 62.78; H, 8.04; N, 3.85. Found: C, 62.69; H, 8.08; N, 3.77.
Selected 1H NMR data (CDCl3): δ 10.00 (1H, d, J ) 3.6 Hz);
4.45 (1H, dd, J ) 3.6, 5.9 Hz); 4.44 (1H, dq, J ) 2.5, 6.7 Hz);
3.77, (3H, s); 3.67 (1H, dd, J ) 2.5, 5.9 Hz); 1.21 (3H, d, J ) 6.7
Hz). 13C NMR data: δ 200.1, 164.2, 156.5, 117.0, 114.0, 65.2,
63.9, 59.8, 55.5, 25.6, 21.8, 17.8, -4.5, -5.0.
1
residue was analyzed by H NMR spectroscopy for the t:c ratio
determination and was purified by flash chromatography with
a 30:70 Et2O:hexanes mixture as eluant to afford â-lactam 11t,c
(0.079 g, 0.315 mmol, 63% yield) as a 97:3 mixture of t and c
isomers. Evaporation to dryness of the aqueous phase of several
reactions allowed recovery of Yb(OTf)3 that can be recycled (see
text and Table 1, entry 3).
(rR)-Meth yl r,2-Dip h en yl-3-eth yl-4-oxo-1-a zetid in ea c-
eta te (26). The mixture of three isomers was a thick oil. IR:
1755, 1740 cm-1. Anal. Calcd for C20H21NO3: C, 74.28; H, 6.54;
N, 4.33. Found: C, 74.38; H, 6.63; N, 4.19. Selected 1H NMR
data (CDCl3) of the major trans isomer: δ 5.28 (1H, s); 4.09 (1H,
d, J ) 2.4 Hz); 3.00 (1H, dt, J ) 2.4, 8.0 Hz). Selected 13C NMR
data (CDCl3) of the major trans isomer: δ 172.0, 168.5, 61.9,
Gen er a l P r oced u r e for th e Yb(OTf)3-Ca ta lyzed Th r ee-
Com p on en t â-La cta m Syn th esis. The preparation of 1-(4′-
methoxyphenyl)-3-methyl-4-(2-phenylethenyl)azetidin-2-one
(12t,c) in CH3NO2 is illustrative of the procedure. To a stirred
solution of Yb(OTf)3 (0.031 g, 0.05 mmol) in CH3NO2 (2 mL) kept
at rt under nitrogen were added cinnamaldehyde (0.132 g, 1
mmol) in CH3NO2 (2mL) and 4-methoxyaniline (0.123 g, 1 mmol)
in CH3NO2 (2mL). After 10 min of stirring at rt, SKTA 1 (0.141
g, 0.5 mmol) in CH3NO2 (2mL) was added via a cannula. The
mixture was stirred at rt for 15 h. After addition of Et2O and
water the reaction was worked up as described above to afford,
after flash chromatographic purification, â-lactam 12t,c (0.096
g, 0.345 mmol, 69% yield) as a 60:40 mixture of t and c isomers.
â-Lactams 11,2 12,4b 13,2 14,2 16-19,2 24c,s,20 and 24t ,s20
were known compounds and had physical properties and spectral
data in agreement with those reported in the literature. The
relevant 1H NMR data of the two unknown isomers of 24 were
as follows. 24c,a (CDCl3): δ 4.30 (1H, dt, J ) 6.0, 7.7 Hz); 4.10
(1H, t, J ) 5.8 Hz); 3.31 (1H, m). Of 24t,a (CDCl3): δ 4.41 (1H,
dt, J ) 3.8, 6.8 Hz); 3.87 (1H, dd, J ) 2.2, 3.8 Hz); 3.04 (1H, dt,
J ) 2.2, 6.1 Hz).
1
61.5, 59.9, 52.5, 21.4, 11.2. Selected H NMR data of the minor
trans isomer: δ 5.45 (1H, s); 4.60 (1H, d, J ) 2.2 Hz); 2.94 (1H,
dt, J ) 2.2, 7.0 Hz). Selected 13C NMR data of the minor trans
isomer: δ 172.2, 170.0, 62.1, 61.5, 58.4, 52.3, 21.6, 11.4. Selected
1H NMR data of the cis isomer: δ 5.22 (1H, s); 4.78 (1H, d, J )
5.7 Hz); 3.30 (1H, dt, J ) 5.7, 7.3 Hz). Selected 13C NMR data
of the cis isomer: δ 172.0, 168.7, 60.5, 59.9, 56.5, 52.4, 18.8, 12.0.
Ack n ow led gm en t. Partial financial support by
MURST and CNRsPiano Strategico Tecnologie Chimiche
Innovative is gratefully acknowledged. O.S. thanks the
Deutsche Forschungsgemeinschaft for a postdoctoral
fellowship.
J O960844U